Breast cancer is among one of the most common cancers that occur in women in the United States; it accounts for one in four female cancers, making it one of the most important cancers in the Western world. Breast cancer results from the abnormal growth of the mammary gland, which is regulated by the female hormone, estrogen. The activity of estrogen is mediated by the estrogen receptor (ER) which in turn regulates the expression of genes necessary for the growth and development of the mammary gland. The presence or absence of the ER serves as a key prognostic marker in breast cancer development. The majority of breast cancers initially develop as hormone dependent, which implies that the presence of estrogen can enhance the progression of the cancer. However, hormone responsive breast cancers frequently develop into more aggressive phenotypes that are hormone independent. In many cases, the ER is still present, but its role in hormone refractory tumorigenesis is unclear. A potential mechanism for the development of hormone refractory breast cancer may involve endocrine disruptors, including heavy metals such as cadmium. Cadmium is an environmental contaminant that enters the body through the diet or cigarette smoke. It affects multiple cellular processes, including cell proliferation, differentiation and apoptosis. Cadmium has been implicated by several studies to function as a metalloestrogen and has the ability to bind and activate ER1. Our own studies along with others have recently shown that cadmium can stimulate ER target gene expression. Additionally, we have demonstrated that cadmium potentiates the molecular cross-talk between ER1 and transcription factors like c-jun to regulate the expression of cadmium-induced genes. While acute cadmium exposure is known to activate the estrogen receptor and promote cell growth, the consequence of chronic cadmium exposure is unclear. Since these heavy metals tend to bioaccumulate, it is necessary to understand and elucidate the effects of prolonged cadmium exposure on breast cancer progression. Studies have shown that exposure to cadmium is associated with development of more malignant tumors. My lab's preliminary findings also suggest that chronic cadmium exposure can enhance breast cancer cell growth and migration. This leads me to hypothesize that chronic cadmium exposure may promote the development of more aggressive breast cancer. Results from this study will provide a better understanding of how cadmium contributes to the progression of breast cancer and offer insights into its mechanism of action. Results obtained from this research will have significant clinical contributions, including screening for heavy metal toxicities, identifying heavy metal-associated breast cancer cases, developing expression profiles of tumors exposed to high concentrations of cadmium, and designing more effective treatments for hormone- refractory breast cancer cases. PUBLIC HEALTH RELEVANCE: The objectives of this study are to 1) characterize the effects of chronic cadmium exposure on the progression of breast cancer, 2) determine if there is a correlation between cadmium levels and tumor pathology, and 3) identify the gene expression profile associated with cancer cells exposed to prolonged periods of cadmium. Results from this study will not only provide a better understanding of how prolonged exposure of environmental contaminants such as cadmium can promote breast cancer progression, but also offer new insights into the mechanism of action. Additionally, the results obtained from this research will have significant clinical contributions, including screening for heavy metal toxicities, identifying heavy metal-associated breast cancer cases, developing expression profiles of tumors exposed to high cadmium levels, and designing more effective treatments for hormone-refractory breast cancer cases.